The global outbreak of SARS in 2002-2003 was caused by the infection of a new human coronavirus SARS-CoV. The infection of SARS-CoV is mediated mainly through the viral surface glycoproteins, which consist of S1 and S2 subunits and form trimer spikes on the envelope of the virions. Here we report the ectodomain structures of the SARS-CoV surface spike trimer in different conformational states determined by single-particle cryo-electron microscopy. The conformation 1 determined at 4.3 resolution is three-fold symmetric and has all the three receptor-binding C-terminal domain 1 (CTD1s) of the S1 subunits in "down" positions. The binding of the "down" CTD1s to the SARS-CoV receptor ACE2 is not possible due to steric clashes, suggesting that the conformation 1 represents a receptor-binding inactive state. Conformations 2-4 determined at 7.3, 5.7 and 6.8 resolutions are all asymmetric, in which one RBD rotates away from the "down" position by different angles to an "up" position. The "up" CTD1 exposes the receptor-binding site for ACE2 engagement, suggesting that the conformations 2-4 represent a receptor-binding active state. This conformational change is also required for the binding of SARS-CoV neutralizing antibodies targeting the CTD1. This phenomenon could be extended to other betacoronaviruses utilizing CTD1 of the S1 subunit for receptor binding, which provides new insights into the intermediate states of coronavirus pre-fusion spike trimer during infection.
Oxidative stress plays a central role in the pathogenesis of various neurodegenerative diseases. Increasing evidences have demonstrated that structural abnormalities in mitochondria are involved in oxidative stress related nerve cell damage. And Drp1 plays a critical role in mitochondrial dynamic imbalance insulted by oxidative stress-derived mitochondria. However, the status of mitochondrial fusion and fission pathway and its relationship with mitochondrial properties such as mitochondrial membrane permeability transition pore (mPTP) have not been fully elucidated. Here, we demonstrated for the first time the role of Cyclophilin D (CypD), a crucial component for mPTP formation, in the regulation of mitochondrial dynamics in oxidative stress treated nerve cell. We observed that CypDmediated phosphorylation of Drp1 and subsequently augmented Drp1 recruitment to mitochondria and shifts mitochondrial dynamics toward excessive fission, which contributes to the mitochondrial structural and functional dysfunctions in oxidative stress-treated nerve cells. CypD depletion or over expression accompanies mitochondrial dynamics/functions recovery or aggravation separately. We also demonstrated first time the link between the CypD to mitochondrial dynamics. Our data offer new insights into the mechanism of mitochondrial dynamics which contribute to the mitochondrial dysfunctions, specifically the role of CypD in Drp1-mediated mitochondrial fission. The protective effect of CsA, or other molecules affecting the function of CypD hold promise as a potential novel therapeutic strategy for governing oxidative stress pathology via mitochondrial pathways. (C) 2016 Elsevier Inc. All rights reserved.
ObjectivesTo systematically review the clinical characteristics of pregnant females and juveniles (<18 years) with Middle East Respiratory Syndrome (MERS), so as to provide evidence for epidemic prevention and treatment of COVID-19.MethodsPubMed, EMbase, Web of Science, The Cochrane Library, CNKI, VIP and WanFang Data databases were electronically searched to collect studies on clinical characteristics of pregnant females and juveniles with MERS from inception to February 15th, 2020. Two reviewers independently screened literature, extracted data and assessed risk of bias of included studies. Descriptive analysis was then performed.ResultsA total of 12 studies involving 12 pregnant females, and 21 juveniles with MERS were included. The results of studies showed that the male to female ratio of juveniles patients was 1 to 1.63 and the age ranged from 9 months to 16 years. The primary transmission route of juveniles cases was family contact infection, accounting for 57.1% (12/21). Asymptomatic juveniles accounted for 57.1% (12/21), and the most common symptoms were fever, cough and shortness of breath. Some patients exhibited gastrointestinal symptoms such as vomiting and diarrhea. The positive rate of MERS-CoV RCT test was 100.0% (21/21). As for chest radiograph, 73.7% (14/19) cases showed no obvious lesions, and juveniles with lesions were mainly bilateral. 3 patients with underlying diseases developed severe cases, the mortality was 9.5% (2/21). The age range of pregnant women was 27 to 39, with the gestational age from 6 to 38 weeks. The primary transmission route for pregnant women was nosocomial infection, accounting for 57.1% (4/7). Fever, cough, shortness of breath were common manifestations, while abdominal pain occurred in two female patients. The positive rate of MERS-CoV RCT test was 100.0% (11/11). The chest radiograph findings were mainly bilateral lesions, accounting for 55.6% (5/9). 80.0% of whole pregnant females were severe cases (8/10), 4 of them died, with the 50.0% (4/8) mortality in severe pregnant cases. Among the infective pregnant women, 2 were stillborn and 10 were delivered, of which 1 died due to premature delivery. The remaining 9 surviving newborns were not infected with MERS-CoV and there was no evidence of mother-to-child transmission.ConclusionsThe clinical symptoms of MERS in juveniles are similar to those in adults, however, considerably milder. Severe case rate is higher in patients with underlying diseases. However, maternal infections could be much severe with higher mortality. It is particularly important to strengthen the management of pregnant females, especially prevent hospital infection. There is still no evidence of MERS-CoV mother-to-child transmission.